Implantable prosthetics such as prosthetic heart valves can be used to replace damaged or diseased tissues. For instance, prosthetic heart valves may be used to replace natural valves including aortic, mitral, and pulmonary valves. The predominant types of prosthetic heart valves are either mechanical valves or bioprosthetic valves. Bioprosthetic valves include allograft valves, which include biomaterial supplied from human cadavers; autologous valves, which include biomaterial supplied from the individual receiving the valve; and xenograft valves, which include biomaterial obtained from non-human biological sources including pigs, cows or other animals.
Presently, mechanical valves have the longest durability of available replacement heart valves. However, implantation of a mechanical valve requires a recipient to be prescribed anticoagulants to prevent formation of blood clots. Unfortunately, continuous use of anticoagulants can be dangerous, as it greatly increases the user's risk of serious hemorrhage. In addition, a mechanical valve can often be audible to the recipient and may fail without warning, which can result in serious consequences, even death.
The use of bioprosthetic heart valves (BPHVs) in valve replacement procedures is often preferred as BPHVs do not require ongoing patient treatment with anticoagulants. Allograft transplants have been quite effective, with good compatibility and blood flow characteristics in the recipients. However, the availability of human valves for transplantation continues to decline as a percentage of cardiac surgeries performed each year. As such, the choice of xenograft materials for use in replacement BPHVs is becoming more common.
Both xenografts and allografts require that the graft biomaterial be chemically fixed prior to use in order to render the biomaterial more non-antigenic as well as to improve resistance of the biomaterial to degradation. Currently, glutaraldehyde fixation of xenograft and allograft biomaterial is used. Glutaraldehyde fixation forms covalent cross-links between free amines in the tissue proteins. Glutaraldehyde is commonly used alone as well as in combination with a variety of other compounds in stabilizing tissues for implant. For instance, traditional glutaraldehyde fixation methods are adequate for fixing certain tissue proteins, and in particular, collagen, but this method is not adequate for fixing other extra cellular matrix components of a tissue. For example, glycosaminoglycans (GAGs) are not fixed via glutaraldehyde crosslinking regimes. As GAGs of the spongiosa layer can act as a cushion between the outer fibrosa and ventricularis layers during function, the leaching of GAGs from implantable materials can lead to reduced bending stiffness and ultimately to degenerative failure of the implant. Attempts have been made to stabilize GAGs in implantable tissues. While these methods have shown some success in preventing degradation of implant materials, room for improvement exists.
Stabilization regimes used alone or in conjunction with glutaraldehyde fixation protocols include use of polyepoxy amines for crosslinking a variety of amino acid residues found in tissue proteins (see, e.g., U.S. Pat. No. 6,391,538 to Vyavahare, et al., which is incorporated herein by reference), use of phenolic tannins for elastin fixation (see, e.g., U.S. Patent Application Publications 2004/0153145 to Simionescu, et al., which is incorporated herein by reference), and use of various chemistries including carbodiimide chemistry for stabilization of glycosaminoglycans in biological tissues (see, e.g., U.S. Pat. No. 6,861,211 to Levy, et al., which is incorporated herein by reference).
Despite advances in addressing the needs for longer lasting and better performing implantable bioprosthetics, there remains room for variation and improvement within the art.